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Two highlights for me werel a talk at the University of Toronto, under
the aegis of the Center for Inquiry, on Science in an age of
Endarkenment. And the Riker Memorial Lecture at Oregon Health and
Science University. More>

Anti-nutty professor warns we are living in a time of 'Endarkenment' More>

Tyler Anderson/National Post, Canada

Professor D Colquhoun, FRS
held the established (A.J. Clark) chair of Pharmacology at UCL, and was
the Hon. Director of the Wellcome Laboratory for Molecular
Pharmacology. In October 2004, he became a Research Fellow. Like many previous holders
of the chair (in particular, A.J. Clark, J.H. Gaddum, H.O. Schild and
J.W. Black) his interests are in quantitative analysis of receptor
mechanisms.

He graduated from Leeds with a BSc and
then went to Edinburgh to work for a PhD. After doing research at
University College from 1964-69 on immunological problems and completing
a book on statistics, he went to Yale University to work on nerve
conduction. After returning from the USA he eventually returned to the
Pharmacology Department at UCL in 1979, and has worked on single ion
channel mechanisms since then. [interview][bio]

In 2004, he was made an Honorary Fellow of University College London.

Research

Transmission of an impulse from one nerve cell to another, or to a muscle cell, occurs by the release of a chemical substance, such as acetylcholine or glutamate, which combines with specific protein molecules- receptors- in the membrane of the downstream cell. These receptors form molecular pores which span the cell membrane, and the combination of the transmitter with them causes the pore to open, which allows the passage of sodium and other ions. The current caused by movement of these ions across the membrane then initiates an electrical impulse. We are studying the receptors for glutamate, acetylcholine and glycine by a combination of biophysical and molecular biological approaches. We record the currents through individual receptor-channels which are in their natural environment, the membranes of nerve cells from the brain or ganglia. We also record from channels that have been made from cloned DNA and artificially inserted into a convenient cell membrane. The latter method has the advantage that (with luck) you know which molecule you are dealing with, and also that altered receptors can be made by mutating the amino acid sequence of the receptor proteins. These methods allow us to address a variety of questions. A major question that concerns us is the exact molecular nature of the receptors that occur in living cells in various parts of the nervous system. At a more basic level we are interested in the nature of the molecular interactions that cause the channels to open and shut, and what it is that controls the speed of synaptic events. Once one knows the rates of individual steps in the ion channel reaction mechanism, the binding-gating problem is solved, the way is cleared for rational interpretation of the effects of mutations in the receptor protein, and the response to any arbitrary time course of synaptic concentration of transmitter can be calculated. We have taken this approach to analysis of natural disease-causing mutations in human muscle nicotinic acetylcholine receptors, and in human glycine receptors (the latter being in collaboration with Sivilotti's lab).

Analysis and theory

We have also been closely involved in developing new methods for the analysis of single channel recordings which, because they originate from single molecules, are random in nature. And, in collaboration with Professor A.G. Hawkes (who does all the difficult stuff), we have developed much of the underlying stochastic theory which is necessary for the interpretation of these recordings. This theory allows us to interpret single channel recordings in which short events are undetected, and most recently has been extended to deal with non-stationary channels, such as those observed after a brief pulse of agonist is applied. This theory has proved essential for the interpretation of our experimental observations. For example, we have been interested in questions such as 'what does an individual activation of an ion channel look like, and how is it related to synaptic currents?', 'how can we understand the effect of mutating an amino acid in the receptor?', and 'how can we tell whether a particular amino acid forms part of the binding site?'. One outcome of the theory has been the development of an optimum method (the HJCFIT program) for estimation of rate constants in a mechanism, with exact correction for missed events).

Summer workshop

Analysis and interpretation of single
ion channel records and macroscopic currents using matrix methods.

We run a summer course in which the necessary mathematical background for the understanding of these methods is taught.

Analysis programs

We have developed, in the course of our work, a number of programs for single channel analysis, for curve fitting and for theoretical calculations. They have a lot of features that are not available in any commercial program, and they are free (for academic users).

Selected Recent Publications:

David Colquhoun (2007) Why the Schild method is better than Schild realised. Trends in Pharmacological Sciences, 28, 608 - 614. [email me for a reprint]. The Schild method allows genuine physical equilibrium constants for competitive antagonists to be obtained from experiments in which complex responses are measured. This paper extends work done in 1973 (here), and gives conditions under which valid results can be obtained. The Schild method may still be valid with multiple agonist binding sites, even when agonist binding sites interact and/or are not identical.

Colquhoun, D. (2007). Classical Perspective. What have we learned from single ion channels? Journal of Physiology, 581, 425 – 427. [Get pdf]More (invited) navel–gazing. It starts “The only problem about being asked to write a perspective on the Colquhoun & Sakmann (1985) paper published in The Journal of Physiology is that I’m not yet sure whether the conclusions of that paper were quite right”. The 1985 paper is here.

David Colquhoun (2007) How to get good science. Physiology News, 69, 12 - 14, [download the pdf]. This is a longer version of comments published in the Times Higher Education Supplement, June 1, 2007. It concerns the bad effects of managerialism and boneheaded assesment methods on the quality, and even the honesty, of science. See also, comments on the Improbable Science blog

Andrew J.R. Plested, Paul J Groot-Kormelink, David Colquhoun, and Lucia G Sivilotti (2007) Single channel study of the spasmodic mutation {alpha}1A52S in recombinant rat glycine receptors. Journal of Physiology 591 (1), 51 – 73 [get pdf]. A study of the spasmodic mutation in the glycine receptor. When interpreted in terms of the 'flip' mechanism, the results suggest that the impairment of the receptor function results largely from a large reduction in the affinity of glycine for the flipped conformation, i.e. a shut conformation of the receptor that can be adopted once the ligand is bound, but precedes the opening of the channel. This removes the apparent 'cooperativity of binding', and provides a new way of looking at receptor function. This paper was accompanied by a commentary on the new proposal by Joe Henry Steinbach

Joe Henry Steinbach (2007). A slip 'twixt the cup and the lip: a new way to impair function of transmitter-gated channels. [Get pdf]

Schorge, S., Elenes, S. & Colquhoun, D. (2005). Maximum likelihood fitting of single channel NMDA activity with a mechanism composed of independent dimers of subunits Journal of Physiology 569, 395 – 418. [Get PDF 5.9Mb]Our best shot at kinetic analysis of an NMDA receptor. We find an opening rate for the channel that is much faster than that found by other labs, probably because our analysis methods can detect fast shut times (see Fig. 11).

Colquhoun, D. (2005). From Shut to Open: What Can We Learn from Linear Free Energy Relationships?. Biophysical Journal, 89, 3673–3675. [Get pdf (0.1 Mb)].This is a commentary on a paper in the same issue (Zhou, Y., J. E. Pearson, and A. Auerbach, 2005. Biophys. J. 89, 3680–3685) that attempts to use an explicit reaction scheme as an aid to interpretion of phi–analysis. Methods for detection of intermediates between resting and open states are discussed.Erratum. The allusion to unliganded gating should have cited Grosman, C. (2003), Biochemistry, 42, 14977-14987.

Burzomato,Valeria; Beato,Marco; Groot–Kormelink,Paul J.; Colquhoun,David; Sivilotti,Lucia G. (2004). Single–Channel Behavior of Heteromeric a1b Glycine Receptors: An Attempt to Detect a Conformational Change before the Channel Opens. Journal of Neuroscience24, 10924–10940. [Get PDF]First experimental test of the flip model, in which we attempt to resolve a conformation change that occurs before the channel opens. This provides a basis for a new view of the nature of partial agonists, and the nature of agonist efficacy.

Book Reviews

Colquhoun, D. (2007). Perceptions of a Receptor. A book review, of Nicotinic Acetylcholine Receptors by Jen-Pierre Changuex and Stuart J. Edelstein. (18 Feb 2007, Science, 315, 1079) [Get pdf from Science, or download]“I like history. Nothing gives one a better feel for a subject than knowing how it developed. Nicotinic Acetylcholine Receptors concentrates on the French contribution to knowledge about these neurotransmitter receptors, and it’s a good (if, at times, idiosyncratic) read.” . . . “The account Changeux and Edelstein provide in Nicotinic Acetylcholine Receptors is very good in parts. Nonetheless, as an overall view of the current state of our understanding, it is not only incomplete but sometimes positively misleading.”

Colquhoun, D. (2006). Playing the numbers game. A book review, of Does Measurement Measure Up? How Numbers Reveal and Conceal the Truth by John M. Henshaw. (7 July 2006, Nature, 442, 357) [Get pdf]“This leads to absurd results, like university courses in homeopathy (yes, there are some) being given near-perfect scores when they should really be referred to the Office of Fair Trading for describing as science a subject that is more akin to magic. The antics of the press in their attempts to rank universities are a more-or- less honest attempt to make money. The reification imposed by the QAA is an intellectual disgrace.”

Bits of History

Colquhoun, D. (2006). The quantitative analysis of drug–receptor interactions: a short history. Trends in Pharmacological Sciences, March 2006. [Get pdf]Another short history. I was asked to write about 'receptor theory', but I dislike that term because it sounds (and often is) divorced from experimental realities, and does not distinguish between physical and empirical descriptions. This history is about 8 or 10 people who have contributed the most to physical descriptions of receptors. It traces also the origins of ideas about competitive antagonists.

Colquhoun, D. (2006). Agonist–activated ion channels. British Journal of Pharmacology, (2006) 147, S17–S26. [Get pdf]This short history looks at ion channels as an example of the pharmacologist’s stock in trade, the action of an agonist on a receptor to produce a response.

Colquhoun, D. (2005). Stephenson, affinity and efficacy in 2005. pA2 online, volume 3 Issue 4 pp. 5–8. [Get pdf]The death last year of Robert Stephenson provides a good excuse to take a look at the current status of his ideas, and to recall the Pharmacology department in Edinburgh in the 1960s.

Colquhoun, D. (2007) Should NICE evaluate complementary and Alternative Medicine? British Medical Journal, 337, 508 – 509. [Get pdf].A debate in the BMJ in which the theory is advanced that the reason that CAM has still not been referred to NICE is that CAM sympathisers in the Department of Health know that it would fail. See also the comments on the debate.

Colquhoun, D. (2007) Treating Critically Ill Patients With Sugar Pills, Chest, 131, 645. [Get pdf].This is a letter to the official journal of the American College of Chest Physicians, sent after they published an article that purported to show that homeopathic potassium dichromate (i.e. water) was a useful way to treat patients in intensive care. No, that is not a joke!

Colquhoun, D. (2005) Homoepathy: a relict ot the past. Focus Altern. Complement. Ther. 2005; 10: 278–80. [Get PDF]This is a contribtion to a debate in Edzard Ernst's journal, Homoeopathy: relic of the past or medicine of the future? (Marking Samuel Hahnemann’s 250th anniversary). It proposes that homeopathy is but one example of a wider fashion for delusional behaviour.

Colquhoun, D. (2005) Abuse of Prisoners at Abu Ghraib. Science307,1873. [Get PDF][Get PDF of Fiske et al.]A letter that, along with three others, was published as a response to an article by Fiske et al. that appeared to defend Abu Ghraib behaviour as 'normal'.

Colquhoun, D. ( 2004) Too Many 'Omics (letter). The Scientist Volume 19 | Issue 3 | 8 | Feb. 14, [Get PDF] Latest news: is this the craziest example yet? The "Resourceome" —"the full set of bioinformatics resources". For this one you can blame What Inspired You? A survey by Spiked-Online.Yet more navel-gazing by the elderly.